Oxidative stress is a major cause of autonomic dysregulation, increased blood pressure (BP) and end-organ damage in hypertension. Methionine sulfoxide reductase A (MsrA) is a unique anfioxidant that enables redox signaling and protects against oxidative damage by selectively reversing oxidation of methionine residues in proteins. We reasoned that the targeted prevention of methionine oxidation might yield a phenotype distinctively different than the general antioxidants superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). In preliminary experiments, we found that MsrA-/- mice exhibit autonomic dysregulafion, increased sympathetic nerve activity (SNA), hypertension and aortic aneurysm formation. These phenotypes have not been observed in mice deficient in SOD or GPx. While protecfive actions of MsrA have been demonstrated in aging, neurodegeneration, and myocardial ischemia/infarcfion, its roles in autonomic regulation, hypertension and vascular damage have not been invesfigated. We hypothesize that: 1) MsrA is required for normal autonomic and BP regulation and protects against angiotensin II (Ang ll)-induced hypertension and end-organ damage via actions at both the end-organ and the brain to reduce SNA; and 2) the mechanisms include inhibition of oxidative stress and inflammation. Project aims are to: (1) Determine cardiovascular, autonomic and end-organ phenotypes in global MsrA knockout, transgenic and control mice before and during systemic infusion of Ang-ll; (2) Deflne the roles of targeted MsrA expression and deletion in nervous system vs. vascular muscle; and (3) Determine the CNS contributions of oxidative stress, inflammation, and the renin-angiotensin system to increased SNA, hypertension, and end-organ damage in MsrR-/- mice. Cardiovascular and autonomic phenotypes will be fully characterized. Inflammation, oxidative stress, cytokines and associated expression of pro- and antioxidant genes will be measured in heart, aorta and speciflc brain sites. MsrA expression will be modifled in a tissue- and site-speciflc manner using gene targeting and viral-mediated gene transfer of MsrA and siRNA-MsrA. Central mechanisms will be evaluated by measuring responses to intracerebroventricular infusions ofthe antioxidant tempol, the ATi receptor blocker losartan, and the sympatho-inhibitory drug rilmenidine. The signiflcance ofthis speciflc methionine reductase as a novel, protective regulator of autonomic activity and end-organ integrity relates to its potential as a therapeutic target for treatment of hypertension. RELEVANCE (See instructions): Oxidative stress contributes to many age-related diseases including hypertension. The finding that MsrA exerts powerful protective actions in the nervous system and peripheral tissues like arterial blood vessels identify it as a novel determinant of autonomic regulafion and end-organ damage, and a potenfial therapeufic target in hypertension.